Cocaine abuse in women during the postpartum period is associated with dysfunctional maternal care, which can have severe lifelong consequences for the child. The preclinical model used in the following experiments employs a dual-choice paradigm based on the conditioned place preference procedure to offer postpartum maternal rats a choice between environments associated with pups and cocaine. In some females, cocaine is reinforcing enough to compete with maternal motivation for pups, whereas in others maternal motivation is the stronger, more resilient force. We identified neurons within discrete brain regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NA) and medial preoptic area/ventral bed nucleus of the stria terminalis (mPOA/vBST) that are differentially activated when postpartum rats express a motivated preference for cocaine- or pup-associated environments. The proposed research project is part of an ongoing research project funded by a NARSAD Young Investigator Award, designed to test the hypothesis that preference for pups versus cocaine-associated environments is regulated by the concerted activity of regionally distributed networks of neurons in the regions mentioned above. We will determine the functional role of these sites in the expression of motivated choices by transiently inactivating (bupivacaine infusion) each of them and then testing stimulus-associated environment preference (Specific Aim I). Immunocytochemical analysis of the early immediate gene product cFos will reveal regional specificity of neuronal inactivation, and consequent changes in neuronal activity within the remaining key components of the motivational circuitry (Specific Aim II). Further, the causal contribution of dopamine (DA) and glutamate (GLU) neurotransmission within key regions to the choice behavior will be determined with site- specific infusion of selective DA and GLU agonists and/or antagonists (Specific Aim III). These experiments will uncover which regions are causally involved in the motivated choice responses of pup- and cocaine-seeking behaviors, and further reveal how these CNS sites interact to promote the choice for one stimulus over the other. PUBLIC HEALTH RELEVANCE: The 2007 National Survey on Drug Use and Health (NSDUH) estimated the rate of cocaine use among pregnant women at 5.2%. Cocaine abuse in women during pregnancy and the postpartum period severely disrupts mother-infant interactions, which can have negative lifelong consequences for both members of the dyad, often including severe mental health consequences. Substance abuse remains a pressing public health problem that affects millions of women and their babies, and imposes enormous financial and social burdens on society. This application is focused in the understanding of the neural substrate that mediates the motivational aspects of maternal behavior during the postpartum period, particularly within the context of the disruptive effects of drugs with high abuse potential such as cocaine. Through a combination of neurobiological and behavioral techniques, this project will uncover which brain regions are causally involved in the motivated choice responses of pup- and cocaine-seeking behaviors, and further reveal how they interact to promote the preference for one stimulus over the other. Stimulant abuse is an insidious and dangerous chronic recurring and relapsing disease. While the human condition is vastly more complex than our preclinical model, our data offer critical information of the fundamental neurobiological underpinning of the disruptive effect of cocaine on maternal motivation. This preclinical information might contribute to the development of strategies for treatments or methods of prevention of this tragic human condition, with particular emphasis in maintaining or restoring mother- infant bonding.